Today we know that the phenotype of all mammals - from rodents, to non-human primates to humans - is driven by the metagenome, the combination of the host genome and the microbial genome. In the natural world, the microbiomes of free-living mammalian organisms, including wild mice and humans, co-evolved with their respective hosts under evolutionary pressure in regard to inflammatory immune stimuli such as infectious pathogens, but also toxins and mutagens. Based on the hypothesis that natural microbiota shaped by evolution in a challenging environment promote the fitness and survival of their host, upon whom they depend, we propose that standard laboratory mice lack physiologically important microbes present in natural microbiota and absent in laboratory microbiota and that this may limit their ability to model complex diseases of humans and other free-living mammals. We set out to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart but could be transferred to and maintained in laboratory mice over several generations (Cell 2017;171:1015-102). In a follow up study, we aimed to create a model with natural microbiota and pathogens at all body sites. This was achieved by transferring C57BL/6 embryos into wild mice. The offspring gave rise to a colony of C57BL/6 mice, which we call wildlings. Wildlings resembled wild mice and differed substantially from conventional laboratory mice with regard to their bacterial microbiome at important epithelial barrier sites (gut, skin, and vagina), their gut mycobiome and virome, and their level of pathogen exposure. The natural microbiota of wildlings were stable over multiple generations and resilient against antibiotic, dietary, and microbial challenges. To test the translational research value of wildlings in a retrospective bench-to-bedside approach, we repeated well-documented, rodent-based studies that had failed upon transitioning to clinical trials in humans. We chose the CD28-superagonist (CD28SA) trial as representative for treatments targeting adaptive immune responses and antitumor necrosis factoralpha (TNF-a) treatment (anti-TNF-a or TNF-receptor: Fc fusion protein) during endotoxemia as a representative for treatments targeting innate immune responses. In both preclinical studies, wildlings, but not conventional laboratory mice, phenocopied human immune responses. Given the wide-ranging effects of microbiota on host physiology, natural microbiota-based models may benefit different research fields (e.g., metabolism and neurodegenerative diseases) and may also be applicable to other animals. Such models may enhance the validity and reproducibility of biomedical studies among research institutes, facilitate the discovery of disease mechanisms and treatments that cannot be studied in regular laboratory mice, and increase the translatability of immunological results to humans.